Background for the Atorvastatin Studies[unreadable] [unreadable] The inflammation of sarcoidosis is thought to be driven by highly polarized Th1 immune responses. Hydroxymethylglutaryl-coenzyme a (HMGCoA) reductase inhibitors, known as statins, were initially developed to reduce blood cholesterol and improve survival in patients with cardiovascular disease, but additional studies indicated that statins produced salutary effects which were independent of changes in serum cholesterol and might be related to inhibition of immune/inflammatory responses. More importantly, with respect to sarcoidosis, statins have been reported to suppress Th1 and enhance Th2 immune responses. Statins have also been reported to produce beneficial clinical effects in murine models of experimental autoimmune myocarditis (EAM) and experimental autoimmune encephalomyelitis (EAE) (both of which are characterized by polarized Th1 immune responses), and, more recently, in a small number of human patients with rheumatoid arthritis.[unreadable] [unreadable] In 2003, in collaboration with Dr J. Farber, we applied for, and were awarded, a competitive Bench to Bedside Award by the NIH Office of Rare Diseases and the NIH Clinical Center to study effects of atorvastatin in the treatment of pulmonary sarcoidosis. We first studied the effects of statins in isolated inflammatory cells, including alveolar macrophages from patients with pulmonary sarcoidosis. In addition, we designed a randomized, double-blind, placebo-controlled trial to determine if atorvastatin can reduce the need for steroids by patients with pulmonary sarcoidosis.( Clinical Protocol (NHLBI06-H-0072): Atorvastatin as a disease modifying agent in Stage II and Stage III Pulmonary Sarcoidosis: A randomized, double blind, placebo-controlled trial.)[unreadable] [unreadable] Results of Atorvastatin Studies[unreadable] [unreadable] Since formation of sarcoid granulomas may be driven by highly polarized Th1 immune responses, effects of atorvastatin were studied on expression of co-stimulatory and activation molecules in blood monocyte-derived human dendritic cells (DC), and on differentiation of nave T cells from human umbilical cord blood. Flow cytometry measurements indicated that, in DC, 50 uM atavastatin or mevastatin reduced LPS (bacterial lipopolysaccharide)-induced expression of CD86, CD83, CD80 and HCA-Dr. In nave T lymphocytes, purified from human umbilical cord blood, 1uM atorvastatin reduced the percentage of CD4+ Th1 cells that expressed CXCR3 receptors or IFN&#947;. Effects of statins in DC and lymphocytes were reversed by mevalonate, suggesting that HMG-CoA reductase was the site of atorvastatin action. To assess the potential therapeutic utility of statins in sarcoidosis, effects of atorvastatin were assessed on the production of cytokines and chemokines in alveolar macrophages from four consecutive sarcoid patients (not on immunosuppressive medications). In these cells, 30 uM atorvastatin inhibited production of IP-10, Mig, MCP-1, MIP-1&#945;, and MIP-1&#946;. Thus, by decreasing expression of co-stimulatory and activation molecules in DC, and by suppressing CD4+ T cell differentiation and chemokine production in alveolar macrophages, statins might have beneficial effects in Th1 polarized conditions such as sarcoidosis. [unreadable] [unreadable] [unreadable] Clinical Protocol (NHLBI 06-H-0072): Atorvastatin as a disease modifying agent in Stage II and Stage III Pulmonary Sarcoidosis: A randomized, double blind, placebo-controlled trial.[unreadable] [unreadable] Principal Investigator: Joseph Fontana, M.D., Staff Physician, PCCMB[unreadable] [unreadable] Associate Investigator: Vincent Manganiello, M.D., Ph.D.[unreadable] Chief, Section in Biochemical Physiology[unreadable] [unreadable] Medically Responsible Investigator: Joel Moss, M.D., Ph.D., Chief, PCCMB[unreadable] [unreadable] Precis[unreadable] Background: Sarcoidosis is a multi-system granulomatous inflammatory disease. Pulmonary involvement is most common. Patients typically experience fatigue, weakness and dyspnea. Respiratory muscle weakness, which may be secondary to granulomatous inflammation, is associated with dyspnea and decrease quality of life (QOL). The disease can remit spontaneaously or become chronic, with exacerbations and remissions. In some patients, it can progress to pulmonary fibrosis and death. Granulomatous inflammation is characterized primarily by accumulation of monocytes, macrophages and activated T-lymphocytes, with increased production of key inflammatory mediators, TNF-&#945;, INF-&#947;, IL-2 and IL-12, characteristic of a Th1-polarized response (T-helper lymphocyte-1 response). Corticosteroids are the current mainstay of treatment, but their long-term benefits are not certain. Because steroids often produce undesirable side effects, investigations to identify alternative therapies are warranted. There is sufficient evidence to test the proof of concept that pathways targeted by statins will have a therapeutic effect in sarcoidosis, since, in pre-clinical studies, statins blunt Th1-mediated inflammatory responses.[unreadable] [unreadable] Aims:The study involves a double-blind placebo-controlled, randomized trial which aims to determine if atorvastatin administration results in less steroid use and longer steroid-free intervals in patients with pulmonary sarcoidosis who require prednisone treatment.[unreadable] [unreadable] Methods:Patients, who are 18-70 years old, with stage II or III pulmonary sarcoidosis, diagnosed by a compatible clinical history and supported by a lung, lymph node, or tissue biopsy, will be enrolled in the study, if they require prednisone therapy. The patients will be randomly assigned to two groups; as prednisone is tapered, one group will receive placebo and the other, atorvastatin. The study drugs will be administered for twelve months, during which time patients will be periodically evaluated as to their clinical status and prednisone requirements. Pill counts and patient diaries will be used to determine the amount of steroid use during the study period. Patients with pulmonary fibrosis > 50% of total lung volume or serve co-morbidities will be excluded from this trial.[unreadable] [unreadable] The primary endpoint is the duration of the steroid-sparing period. Secondary clinical and physiological endpoints are intended to analyze possible anti-inflammatory and beneficial effects of the drugs. Since there is no gold standard outcome measure in sarcoidosis, four categories of secondary endpoints will be used to characterize the effects of the therapeutic agent on the clinical course of the disease: Imaging (high resolution chest CT); quality of life assessments (SF-36, and SGRQ), anti-inflammatory effects (biomarkers and relapse rates), and functional effects (CPET, PFTs). Finally, we will study the utility of exhaled nitric oxide and carbon monoxide in monitoring disease activity.